It is estimated that 1.5 to 2% of the entire population of the world suffers from diabetes mellitus of some type. Diabetes mellitus is a chemical disorder of the human body primarily involving an inability of the body to properly utilize sugar and other chemical compounds in the metabolism of the body. It is characterized by an elevation in the concentration of sugar in the blood and also by the appearance of sugar in the urine.
In general terms, diabetes mellitus is classified into three types, namely, Type I, IGT and Type II. In Type I diabetes, the beta cells in the pancreas, probably through an auto-immune reaction, cease producing insulin into the bloodstream of the person. Insulin is a chemical substance which is normally secreted into the bloodstream by beta cells within the pancreas. Insulin is vitally important to the person because it enables the person to properly utilize and consume sugar in the bloodstream as part of the metabolism process.
In Type I cases, where the pancreas has ceased producing insulin, it is necessary for the afflicted person to inject insulin directly into the bloodstream at prescribed periodic intervals and dosages in order to control the level of sugar in the blood. This is called intravenous injection. Oral ingestion of insulin is also possible but usually less effective due to the degradation of insulin caused by the passage through the stomach and upper intestine.
In IGT and Type II diabetes, the pancreas continues to produce insulin but, some or all of the insulin may fail to bind to the body's cell receptors and/or internalization of insulin in the cells is reduced. In such cases, there may be a sufficient level of insulin in the blood, but the ability of the cells to uptake glucose is reduced or non-existent because of reduced internalized insulin.
The existence of Type I, IGT or Type II diabetes in a person is usually determined by an oral glucose tolerance test (OGTT). OGTT is a test in which the fasting patient is given a known amount of glucose (sugar) by mouth, and the blood is tested at intervals thereafter to note the quantity of sugar in the blood. A curve is then constructed from which important information about the person can be drawn. The glucose tolerance test curve will typically show whether the patient is hyperglycaemic (diabetic) or whether the patient has too little sugar in his or her blood and is therefore hypoglycaemic.
Symptoms of hyperglycaemia can be headaches, increased urination, thirst, nausea, weight loss, fatigue and coma. Hyperglycaemia can be caused by Hypoinsulinism, a condition in which the insulin producing beta cells of the pancreas fail to manufacture insulin or manufacture and secrete a reduced amount of insulin into the bloodstream. In such cases, levels of sugar in the blood are dramatically increased.
Hyperglycaemia can also be caused by failure of some or all of the available insulin in the blood to bind to the body's cell receptors and/or internalization of insulin in the cells is reduced.
Hypoglycaemia (too little sugar) is also a blood condition that diabetics must constantly guard against. The symptoms of hypoglycaemia are abrupt episodes of intense hunger, trembling of the hands and body, faintness, black spots before the eyes, mental confusion, sweating, abnormal behaviour, and, in severe cases, convulsions with loss of consciousness. In such cases, examination of the blood at the time of these attacks will show an extremely low level of circulating sugar in the blood.
Hypoglycaemia can be caused by Hyperinsulinism, a condition in which the insulin producing beta cells of the pancreas manufacture and secrete an excessive amount of insulin into the bloodstream. Levels of sugar in the blood are therefore dramatically reduced.
Transfer of glucose from the blood stream to the body cells is believed to be enabled by the binding of insulin to the cell receptors. Receptor bound insulin then increases the amount of insulin that is internalized in the cell. Internalized insulin results in increased utilization of glucose in the cell and consequently increased metabolism. A drug that sensitizes the surface of a body cell to increase the cell's internalization of insulin or is believed or purported to function by sensitizing a cell to insulin is known herein as an "insulin sensitizer".
The following is a list of drugs that are being or have been tested as insulin sensitizers:
1. BRL-49653 as produced by SmithKine Beecham or by some other advocate. PA1 2. Pioglitazone HCL as produced by Takeda or some other advocate. PA1 3. Troglitazone, Noscal or Resiline as produced by Sankyo, Glaxo Wellcome or Warner-Lambert. PA1 4. MC 555 as produced by Mitsubishi or some other advocate. PA1 5. ALRT 268 as produced by Ligand or some other advocate. PA1 6. LGD 1069 as produced by Ligand or some other advocate. PA1 7. Chromic Picolinate. PA1 8. Diab II.TM. (otherwise known as V-411) or Glucanin and produced by Biotech Holdings Ltd. or Volque Pharmaceutical. PA1 U.S. Pat. No. 4,362,719--Therapeutic Method and Compositions for the Treatment of Juvenile Diabetes Mellitus PA1 U.S. Pat. No. 4,579,730--Pharmaceutical Compositions Containing Insulin PA1 U.S. Pat. No. 4,602,043--Treatment for Hypoglycemia PA1 U.S. Pat. No. 4,696,815--Anti-Diabetic Pharmaceutical Forms and the Preparation Thereof PA1 U.S. Pat. No. 4,708,868--Anti-Diabetic Pharmaceutical Forms and the Preparation Thereof PA1 U.S. Pat. No. 4,826,684--Composition for, and Method of, Treatment of Diabetes PA1 U.S. Pat. No. 4,849,405--Oral Insulin and a Method of Making the Same PA1 U.S. Pat. No. 4,871,739--Substituted 6H-7,8-dihydrothiapyrano (3,2-D)-pyrimidines as Hypoglycemic Agents PA1 U.S. Pat. No. 4,873,080--Oral Anti-Diabetic Pharmaceutical Compositions and the Preparation Thereof PA1 U.S. Pat. No. 4,963,526--Oral Insulin and a Method of Making the Same PA1 U.S. Pat. No. 4,978,667--Substituted 6H-7,8-dihydrothiapyrano (3,2-d)-pyrimidines as Hypoglycemic Agents PA1 U.S. Pat. No. 5,057,517--Piperazinyl Derivatives of Purines and Isosteres Thereof as Hypoglycemic Agents PA1 U.S. Pat. No. 5,187,154--Diagnosis and Treatment of Humans with Diabetes or at Risk to Develop Diabetes PA1 U.S. Pat. No. 5,206,219--Oral Compositions of Proteinaceous Medicaments PA1 U.S. Pat. No. 5,234,906--Hyperglycemic Compositions PA1 U.S. Pat. No. 5,284,845--Use of Oral Diazoxide for the Treatment of Disorders in Glucose Metabolism PA1 U.S. Pat. No. 5,380,526--Antidiabetic Agent and Method of Treating Diabetes PA1 U.S. Pat. No. 5,422,125--Method and Composition for Treatment of Insulin Resistance Syndromes PA1 U.S. Pat. No. 5,424,406--Dihydrochalcone Derivatives which are Hypoglycemic Agents PA1 U.S. Pat. No. 5,444,086--Naphthalenylmethyl Thiophenones as Antihyperglycemic Agents PA1 U.S. Pat. No. 5,468,755--Therapeutic Process for the Treatment of the Pathologies of Type II Diabetes PA1 U.S. Pat. No. 5,478,852--Use of Thiazolidinedione Derivatives and Related Antihyperglycemic Agents in the Treatment of Impaired Glucose Tolerance in Order to Prevent or Delay the Onset of Noninsulin-Dependent Diabetes Mellitus PA1 U.S. Pat. No. 5,510,360--Azolidinediones as Antihyperglycemic Agents PA1 U.S. Pat. No. 5,532,256--New Azolidinediones and Thiadiazolidinediones as Antihyperglycemic Agents PA1 U.S. Pat. No. 5,589,183--Method and Apparatus for Treatment of Neurogenic Diabetes Mellitus, and Other Conditions PA1 U.S. Pat. No. 5,595,763--Tungsten (VI) Compositions for the Oral Treatment of Diabetes Mellitus. PA1 a. A therapeutically effective amount of an orally ingestible insulin which withstands degradation by passage through the stomach and upper intestine of the mammal so that a therapeutically effective level of insulin reaches the bloodstream of the mammal. The addition of the insulin sensitizer is to sensitize the cells of the mammal so as to enhance insulin uptake and/or utilization of glucose by the cells of the mammal thus reducing the orally ingested insulin required for a therapeutic dose, and/or, PA1 b. An injected insulin product. The addition of the insulin sensitizer is to sensitize the cells of the mammal so as to enhance insulin uptake and/or utilization of glucose by the cells of the mammal thus reducing the therapeutic dose required of injected insulin, and/or, PA1 c. A sulfonylurea. The addition of the insulin sensitizer is to sensitize the cells of the mammal so as to enhance insulin uptake and/or utilization of glucose by the cells of the mammal thus reducing the required therapeutic dose of the sulfonylurea, and/or, PA1 d. A biguanide. The addition of the insulin sensitizer is to sensitize the cells of the mammal so as to enhance insulin uptake and/or utilization of glucose by the cells of the mammal thus reducing the required therapeutic dose of the biguanide, and/or, PA1 e. A alpha-glucosidase inhibitor. The addition of the insulin sensitizer is to sensitize the cells of the mammal so as to enhance insulin uptake and/or utilization of glucose by the cells of the mammal thus reducing the required therapeutic dose of the alpha-glucosidase inhibitor.
Intravenous injection is the anathema of all Type I and II diabetics forced to inject insulin. These diabetics today are cursed to a lifelong ritual of having to inject insulin into their bloodstream, usually several times a day, in order to keep the level of insulin in the blood within prescribed levels.
Considerable research is being conducted to develop an insulin which can be orally ingested for the treatment of Type I or II diabetes. Such an orally ingestible insulin would be welcomed by Type I and Type II diabetics because it would no longer be necessary for them to undergo a daily routine of intravenous insulin injections. Unfortunately, to date, an orally ingested insulin has not yet been successfully developed.
A major problem is that stomach acids and gut enzymes of the person destroy most of the orally ingested insulin and hence the amount of ingested insulin that reaches the bloodstream is less than what is therapeutically required for the diabetic to function normally. Time release systems, which protect the insulin while it passes through the stomach and upper intestine, and release the insulin subsequently, are being researched to alleviate this problem. The theory of these time release systems is to incorporate the insulin with appropriate time release mechanisms so the insulin is not released until after the time release-insulin combination has passed through the stomach and the preliminary stages of the digestive process.
IGT and Type II Diabetes can be treated with one or more classes of drugs generally known as hypoglycaemics to reduce blood glucose levels.
One class of hypoglycaemics are known as "sulfonylureas". Trade-marks for commercially available sulfonylureas include Glucotrol, Diabinese, DiaBeta, Micronase, Tolinase and Orinase. Sulfonylureas appear to stimulate the pancreas and increase the production of insulin from the beta cells in the pancreas. Unfortunately, there are potential unfavourable side effects from the use of sulfonylureas. Therefore, the less a patient is required to use a sulfonylurea, the fewer side effects are likely to be experienced by that patient.
Another class of hypoglycaemics are known as "biguanides". Trade-marks for some commercially available biguanides include Metformin and Glucophage. The physiological action of biguanides is not completely understood. However, biguanides may divert glucose before reaching the blood stream thereby reducing blood glucose levels. Biguanides may also increase cell receptor sensitivity. There are potential unfavourable side effects from the use of biguanides by a patient so the less a patient uses a biguanide, the less likely the patient is to experience unfavourable side effects.
A further class of hypoglycaemics is known as the "alpha-glucosidase inhibitors". Trade-marks for some alpha-glucosdidase inhibitors include Precose, Prandase, and Acrabose. These drugs are believed to bind glucose in the gastrointestinal tract thereby reducing glucose absorption. Because there are unfavourable side effects associated with the use of alpha-glucosidase inhibitors, the less a patient uses such drugs, the less the patient is likely to experience unfavourable side effects.
The following U.S. patents are relevant to the art of orally administered insulin: